Introduction

Midostaurin is an antineoplastic agent.

Uses for Rydapt

Midostaurin has the following uses:

Midostaurin is a kinase inhibitor indicated for the treatment of adult patients with newly diagnosed acute myeloid leukemia (AML) that is FLT3 mutation-positive as detected by an FDA-approved test, in combination with standard cytarabine and daunorubicin induction and cytarabine consolidation.

Rydapt Dosage and Administration

General

Midostaurin is available in the following dosage form(s) and strength(s):

Capsules: 25 mg.1

Dosage

It isessentialthat the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

AML: 50 mg orally twice daily with food.1

ASM, SM-AHN, or MCL: 100 mg orally twice daily with food.1

Cautions for Rydapt

Contraindications

Hypersensitivity to midostaurin or any of the excipients.1

Warnings/Precautions

Embryofetal Toxicity

Based on its mechanism of action and findings from animal reproduction studies, midostaurin may cause fetal harm when administered to pregnant women. In animal studies, midostaurin caused embryofetal toxicities, including late embryofetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to the fetus. Verify the pregnancy status of females of reproductive potential within 7 days prior to initiating midostaurin therapy. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose. Advise males with female partners to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose.1

Pulmonary Toxicity

Cases of interstitial lung disease and pneumonitis, some fatal, have occurred in patients treated with midostaurin as monotherapy or with chemotherapy. Monitor patients for pulmonary symptoms. Discontinue midostaurin in patients who experience signs or symptoms of interstitial lung disease or pneumonitis without an infectious etiology.1

Specific Populations

Pregnancy

Risk Summary: Based on mechanism of action and findings in animal reproduction studies, midostaurin may cause fetal harm when administered to a pregnant woman. There are no available data on midostaurin use in pregnant women to inform a drug-associated risk of major birth defects and miscarriage. In animal reproduction studies, oral administration of midostaurin to pregnant rats and rabbits during organogenesis caused embryofetal toxicities, including late embryofetal death and reduced fetal birth weight, with delays in fetal growth at doses lower than the recommended human dose. Advise pregnant women of the potential risk to a fetus.1

The background risk of major birth defects and miscarriage for the indicated population are unknown. Adverse outcomes in pregnancy occur regardless of the health of the mother or the use of medications. In the US general population, the estimated background risk of major birth defects and miscarriage in clinically recognized pregnancies is 2% to 4% and 15% to 20%, respectively.1

Animal Data: When midostaurin was administered to female rats prior to mating and through the first week of pregnancy at a dose of 60 mg/kg/day (approximately 0.1 times the human exposure at the recommended dose based on AUC), there were increases in pre- and post-implantation loss, including total litter loss, resulting in a reduction in the number of live embryos.1

During organogenesis, midostaurin administered at oral doses greater than or equal to 3 mg/kg/day (approximately 0.004 times the human exposure at the recommended dose by AUC) to pregnant female rats caused late embryofetal death. Dilated lateral brain ventricles were observed in offspring of rats given doses greater than or equal to 3 mg/kg/day. Extra rib and reduced fetal birth weight with effects on fetal growth (severe renal pelvic cavitation and widened anterior fontanelle) were observed in the absence of maternal toxicity at the highest dose of 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). Midostaurin administered orally to pregnant rabbits during organogenesis led to maternal toxicity with spontaneous abortions and some delay in fetal growth (reduced fetal birth weight) at doses greater than or equal to 10 mg/kg/day (approximately 0.01 times the human exposure at the recommended dose by AUC).1

In an oral pre- and postnatal development study in the rat, adverse effects upon maternal performance included dams with signs of dystocia and a lower live litter size at 30 mg/kg/day (approximately 0.05 times the human exposure at the recommended dose by AUC). For the F1 offspring, lower body weights, accelerated complete eye opening and delayed auricular startle ontogeny were noted at 30 mg/kg/day.1

Lactation

There are no data on the presence of midostaurin or its active metabolites in human milk, the effect on the breastfed infant, or the effect on milk production. Orally administered midostaurin and its active metabolites pass into the milk of lactating rats within 1 hour of a 30 mg/kg/day dose, with approximately 5 times more in the milk of lactating rats compared to plasma.

Because of the potential for serious adverse reactions in breastfed infants from midostaurin, advise women not to breastfeed during treatment with midostaurin and for at least 4 months after the last dose.1

Females And Males of Reproductive Potential

Pregnancy testing is recommended for females of reproductive potential within seven days prior to initiating midostaurin.1

Midostaurin may cause fetal harm when administered to a pregnant woman Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose.1

Males with female sexual partners of reproductive potential should use effective contraception during midostaurin treatment and for at least 4 months after stopping treatment with midostaurin.1

Based on findings in animals, midostaurin may impair fertility in females and males of reproductive potential. It is not known whether these effects on fertility are reversible.1

Pediatric Use

Safety and effectiveness of midostaurin have not been established in pediatric patients.1

Geriatric Use

Of the 142 patients with advanced SM in clinical studies of midostaurin, 64 (45%) were aged 65 and over, and 16 (11%) were aged 75 years and over. No overall differences in safety or response rate were observed between the subjects aged 65 and over compared with younger subjects. Greater sensitivity of older individuals cannot be ruled out.1

Clinical studies in AML with midostaurin did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects.1

In general, administration for elderly patients should be cautious, based on patient’s eligibility for concomitant chemotherapy and reflecting the greater frequency of concomitant disease or other drug therapy.1

Actions

Mechanism of Action

Midostaurin is a small molecule that inhibits multiple receptor tyrosine kinases. In vitro biochemical or cellular assays have shown that midostaurin or its major human active metabolites (CGP62221 and CGP52421) inhibit the activity of wild type FLT3, FLT3 mutant kinases (ITD and TKD), KIT (wild type and D816V mutant), PDGFRα/β, VEGFR2, as well as members of the serine/threonine kinase PKC (protein kinase C) family.1

Gastrointestinal Adverse Reactions: Inform patients that midostaurin can cause nausea, vomiting, and diarrhea. Advise patients to contact their healthcare provider if these symptoms occur or are persisting despite supportive medications.1

Embryofetal Toxicity: Advise pregnant women and females of reproductive potential of the potential risk to a fetus. Advise females of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose. Advise females to inform their healthcare provider of a known or suspected pregnancy.1

Advise male patients with female partners of reproductive potential to use effective contraception during treatment with midostaurin and for at least 4 months after the last dose.1

Lactation: Advise women not to breastfeed during treatment with midostaurin and for at least 4 months after the final dose.1

Infertility: Advise females and males of reproductive potential that midostaurin may impair fertility.1

Additional Information

AHFS First Release. For additional information until a more detailed monograph is developed and published, the manufacturer's labeling should be consulted. It is essential that the manufacturer's labeling be consulted for more detailed information on usual uses, dosage and administration, cautions, precautions, contraindications, potential drug interactions, laboratory test interferences, and acute toxicity.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.